DESCRIPTION: The goal of this project is to use novel combinatorial methods to isolate receptors for short (6-15 residue) peptides and epitopes in proteins. The receptors themselves will be peptides isolated from libraries made at the DNA level and searched by genetic means. Preliminary results have shown that these peptide-peptide complexes can exhibit extremely high selectivity and modest (micromolar range) affinity. Peptides pulled from libraries that bind other peptide target are potentially useful antibody substitutes if the affinity of binding can be increased or if the non-covalent interaction can be rendered irreversible. Two novel strategies are described to achieve this goal. One is to make use of chemical cross-linking methods that the PI has developed to covalently trap weak equilibria between the library derived peptide and its target. The second is to join the original peptide selected from the library via a linker to another peptide, which was selected to bind the original peptide/target complex. This so-called super-receptor concept should provide receptors that have extraordinary affinity and selectivity for the target epitope. Finally, these highly specific complexes between peptides of modest size are of intrinsic interest from a molecular recognition point of view. Therefore, some of these will be studied in detail using a variety of biophysical techniques, including multi-dimensional NMR. These studies will hopefully lead to a better understanding of how one would design peptide receptors de novo that are able to function in aqueous solution.